Hepatic lipase: The role that hepatic lipase (HL) plays in modulating atherogenic risk is controversial. We and others have shown that despite increased plasma total cholesterol and apoB-containing lipoprotein cholesterol, hepatic lipase (HL) deficiency in apoE-KO (E-KO) and LCAT-Tg mice decreases aortic atherosclerosis, suggesting alternative mechanisms by which HL modulates atherogenesis. Analysis of HL expression by Northern blotting and quantitative RT-PCR revealed previously unknown expression of HL in mouse and human macrophages. To investigate whether HL expression in macrophages alters atherogenic risk, fetal liver transplantations (TX) in E-KO and apoE-KO x HL-KO (E-KO x HL-KO) mice were performed. The plasma lipids, lipoproteins and apolipoproteins levels remained unchanged after TX in all animals. Spontaneous aortic atherosclerosis was increased by 3.5-fold (p<0.05) in E-KO x HL-KO mice TX with E-KO BM compared to control, E-KO x HL-KO TX with E-KO x HL-KO BM. Conversely, atherosclerosis was decreased by 60% in E-KO mice TX with E-KO x HL-KO BM compared to control, E-KO TX with E-KO BM. Thus, expression of HL in macrophages enhanced atherosclerosis without modifying the plasma lipid profile. These data provide a novel mechanism by which HL modulates atherogenic risk in vivo. ABCA1: Generation of Transgenic Mice: The identification of ATP binding cassette transporter AI (ABCA1) as the lipid transporter defective in Tangier disease has generated interest in modulating human plasma HDL levels and atherogenic risk by enhancing ABCA1 gene expression. To investigate the role that increased ABCA1 gene expression plays in HDL metabolism we generated two independent lines of transgenic mice that overexpress human ABCA1 (hABCA1-Tg) approximately 4- and 9-fold. Hepatic and macrophage expression of hABCA1 enhanced macrophage cholesterol efflux to apoA-I, increased plasma cholesterol, cholesteryl esters, free cholesterol, phospholipids, HDL-cholesterol, apoA-I and apoB-100 levels and led to the accumulation of apoE-rich HDL 1 and pre-beta HDL. Kinetic studies using non-degradable CEt and protein labels in hABCA1-Tg demonstrated that ABCA1 delayed the catabolism of apoA-I in both liver and kidney leading to increased plasma apoA-I levels. Although compared to controls, the plasma clearance of HDL-CEt was not significantly altered in hACA1-Tg mice, the net hepatic HDL-Cet delivery was increased by 1.5-fold. In addition, the cholesterol and phospholipid concentrations in hABCA1-Tg bile were increased by 1.8-fold. These findings demonstrate that steady state overexpression of ABCA1 in vivo raises plasma HDL-C and apoA-I levels, facilitates hepatic reverse cholesterol transport and biliary cholesterol excretion and may therefore modify atherogenic risk in humans.